title: A model for transmission of the H3K27me3 epigenetic mark.
abstract: Organization of chromatin by epigenetic mechanisms is essential for establishing and maintaining cellular identity in developing and adult organisms. A key question that remains unresolved about this process is how epigenetic marks are transmitted to the next cell generation during cell division. Here we provide a model to explain how trimethylated Lys 27 of histone 3 (H3K27me3), which is catalysed by the EZH2-containing Polycomb Repressive Complex 2 (PRC2), is maintained in proliferating cells. We show that the PRC2 complex binds to the H3K27me3 mark and colocalizes with this mark in G1 phase and with sites of ongoing DNA replication. Efficient binding requires an intact trimeric PRC2 complex containing EZH2, EED and SUZ12, but is independent of the catalytic SET domain of EZH2. Using a heterologous reporter system, we show that transient recruitment of the PRC2 complex to chromatin, upstream of the transcriptional start site, is sufficient to maintain repression through endogenous PRC2 during subsequent cell divisions. Thus, we suggest that once the H3K27me3 is established, it recruits the PRC2 complex to maintain the mark at sites of DNA replication, leading to methylation of H3K27 on the daughter strands during incorporation of newly synthesized histones. This mechanism ensures maintenance of the H3K27me3 epigenetic mark in proliferating cells, not only during DNA replication when histones synthesized de novo are incorporated, but also outside S phase, thereby preserving chromatin structure and transcriptional programs.
authors.affiliation: Biotech Research & Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen N., Denmark. klaus.hansen@bric.dk
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Hansen
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Bracken
authors.forename: Diego
authors.initials: D
authors.lastname: Pasini
authors.forename: Nikolaj
authors.initials: N
authors.lastname: Dietrich
authors.forename: Simmi S
authors.initials: SS
authors.lastname: Gehani
authors.forename: Astrid
authors.initials: A
authors.lastname: Monrad
authors.forename: Juri
authors.initials: J
authors.lastname: Rappsilber
authors.forename: Mads
authors.initials: M
authors.lastname: Lerdrup
authors.forename: Kristian
authors.initials: K
authors.lastname: Helin
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002384:Catalysis; D002460:Cell Line; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology; D017930:Genes, Reporter; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000166:cytology; D008156:Luciferases / Q000378:metabolism; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D008954:Models, Biological; D009154:Mutation; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; C491488:EED protein, human; D006657:Histones; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C430461:SUZ12 protein, human; D014157:Transcription Factors; D008156:Luciferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D008239:Lysine